The present invention relates to a control unit for flow regulation which is used in conjunction with a collecting tube for determining the uniformity of a dose of drug delivered from a powder inhaler or in conjunction with a (cascade) impactor for determining the distribution of the aerodynamic fine fraction in this delivered dose. The invention also relates to measuring and dose collecting tubes for use in conjunction with the control unit, and a process for determining the above-mentioned parameters using the control unit and collecting tubes.
With regard to the effectiveness of a drug which is released as an inhalable powder from an inhaler (e.g. a single dose inhaler such as the “HandiHaler®” or the “Ingelheim Inhaler” or a multi-dose inhaler), the amount of active substance delivered and its aerodynamic particle size distribution are crucial. These test parameters serve to indicate the quality of the pharmaceutical composition and can be determined in the course of stability tests. The methods of measuring these parameters are standardised in US Pharmacopoeia 24, page 1896 ff. (hereinafter referred to as USP) and European Pharmacopoeia, 3rd Edition, Supplement 2000, page 1540 ff and page 101 ff (hereinafter referred to as EP). The pharmacopoeias specify the physical parameters which are to be maintained during measurement (e.g. the level of suction to be applied in order to deliver the dose of drug) and the basic construction of the devices to be used for these measurements. The EP and USP contain for example the diagrammatic drawings shown in FIGS. 1 and 2.
The principle of determining the quantity of active substance delivered or the aerodynamic particle size distribution is based on the active substance being delivered from an inhaler in a defined flow volume. The quantity of powder released is caught in a special device (dose collecting tube or cascade impactor) and then subjected to quantitative analysis.
As can be seen from FIGS. 1 and 2, the apparatus diagrammatically illustrated in EP/USP consists of a suction unit in the form of a vacuum pump, a two-way magnetic valve controllable by a time switch, a throughflow control valve and a collecting tube or an impactor. The vacuum and two-way magnetic valve, two-way magnetic valve and throughflow control valve and the throughflow control valve and collecting tube or cascade impactor are connected to one another. P1, P2 and P3 show positions where pressure gauges can be mounted.
When carrying out the measurements a defined under pressure is produced in the collecting tube or in the cascade impactor by the suction of the vacuum pump. As a result of the underpressure a specific flow volume flows through the inhaler, causing particles of powder to be drawn out of the inhaler into the dose collecting tube or the impactor. The quantity of active substance collected therein is then quantified by a suitable method, for example HPLC.
In order to be able to carry out the measurements under standardised reproducible conditions, a defined flow volume with which the dosage of drug is delivered from the inhaler must be guaranteed, in particular. The EP/USP specify a flow volume of 4 liters, for example (“required suction volume”). In order to achieve the required suction volume a given underpressure of 4 kPa is applied to the apparatus. The magnitude of the flow volume depends to a great extent on the construction of the apparatus and its components, resulting a particular flow resistance. From the flow volume it is then possible to calculate how long the defined underpressure has to be applied (e.g. how long the magnetic valve in FIGS. 1 or 2 has to be opened) in order to achieve a flow volume of 4 liters in a measuring operation with an attached inhaler (“suction time”; for details see below). Thus, the accuracy of the measurements depends among other things on precisely monitoring the suction time and accurately determining the flow volume. With regard to this latter parameter, the USP/EP lay down the following conditions: the USP specifies a range of ±5% for delivery for a flow volume of 4 l, the flow volume (Q) and the time. In the aerodynamic particle size distribution (PSD) only ±5% is demanded for the time. The EP allows a tolerance of ±5% in the delivery of a flow volume of not more than 100 liters. As for the PSD, a tolerance of ±5% is demanded for the flow volume (Q) and the time.
Apparatus which are suitable for measurements in accordance with the conditions of the EP/USP were not available on the market at the time of the invention. Attempts to produce measuring equipment in-house on the basis of the schematic drawings contained in the EP/USP were initially unsuccessful. In particular, it was found to be impossible to achieve a sufficiently constant flow volume with the apparatus constructed as shown in FIGS. 1 and 2 (internal prior art).
Moreover, the experiments described above showed that whenever the amounts of powder delivered into the collecting tube as samples were small. (e.g. in the range from 4 to 5 μg), there were considerable fluctuations in the subsequent quantitative measurement of the contents of the collecting tube. This was attributable to the fact that powder had penetrated into the area marked P1 in FIG. 1 (connecting point for a pressure gauge) and therefore was not included in the quantitative measurement of the contents of the collecting tube.